In 2012, an estimated 241,740 new prostate cancer (PCa) cases will be diagnosed in the US alone. A large number of these represent indolent tumors unlikely to limit the lifespan of the patient. A recent study has shown that it is necessary to treat 48 men to prevent one death from PCa, suggesting that significant overtreatment exists. Still, many PCa are aggressive, causing an estimated 28,170 mortalities this year. Therefore, a more comprehensive diagnostic approach is needed to differentiate indolent and harmless tumors from aggressive and lethal PCa in individual patients.
The most common way of diagnosing PCa is the transrectal ultrasound (TRUS) guided prostate biopsy. But, standard gray-scale ultrasound is unreliable in differentiating PCa from normal tissues. The biopsy procedures are cancer “blind”, aiming to sample the gland systematically in search of possible tumors. Because PCa is a heterogeneous multi-focal disease, with untargeted biopsy both overdiagnosis of clinically insignificant cancer and underdiagnosis of potentially lethal cancer exist in the population at risk.
Accurate PCa targeted biopsy has the potential to 1) reduce the randomness that yields clinically insignificant cancer and leads to overdiagnosis, and 2) increase the likelihood of sampling the most advanced CSR reducing the underdiagnosis of potentially lethal cancer.
Novel genomic, proteomic, and image biomarkers are currently investigated to more reliably diagnose and assess the aggressiveness of PCa. In addition to other tests and biomarkers of higher specificity, a critical component needed to address this problem is a more reliable way to biopsy the gland.
As mentioned above, the most common way of diagnosing PCa is the transrectal ultrasound (TRUS) guided prostate biopsy. But, standard gray-scale ultrasound provides minimal PCa specific information being unreliable in differentiating PCa from normal gland tissues. The biopsy procedures are cancer “blind”, relying instead on non-targeted template biopsy schemata that aim to sample the gland systematically in search of possible tumors. Yet biopsies do not sample the entire gland because the number of cores is limited (typically 12). For an exhaustive, saturation biopsy the number of biopsy cores is very high making them impractical for most patients and the common transrectal biopsy path.
Because PCa is a heterogeneous multi-focal disease, untargeted biopsies often yield to the detection of small, clinically insignificant tumors and/or miss significant cancers (i.e. >0.5 mL). Moreover, due to limited technology, the common manually-operated TRUS-guided biopsy is difficult and quality control is subjective. Studies have shown the biopsy schema is difficult to define and follow, resulting in biopsy samples that are clustered and miss regions of the gland. While these errors have less impact on the detection of small tumors, the detection rate of clinically significant lesions is worsened. Studies have shown that the histologic grade from TRUS biopsy samples is often underestimated compared to prostatectomy specimens. Systematic TRUS biopsies have typically low sensitivity and low negative predictive value. With untargeted biopsy, both overdiagnosis of clinically insignificant cancer and underdiagnosis of potentially lethal cancer exist in the population at risk.
A noticeable solution to sample significant cancer is cancer-image guided targeting. Accurate biopsy targeting to cancer suspicious regions (CSR) of image abnormality has the potential to 1) reduce the randomness that yields clinically insignificant cancer and leads to overdiagnosis, and 2) increase the likelihood of sampling the most advanced CSR, thereby reducing the underdiagnosis of potentially lethal cancer.
CSR targeting for biopsy relies heavily on the ability of imaging to depict CSRs. Among other imaging modalities, magnetic resonance imaging (MRI) provides the highest spatial and contrast resolution for prostate anatomy. Functional MRI imaging techniques (MR spectroscopy (MRSI), diffusion-weighted (DWI), and dynamic contrast-enhanced (DCE)) have shown substantial potential to complement T2-weighted MRI in improving PCa localization. These imaging approaches and PCa image biomarkers still require further validation and have recognized limitations, including the potential for false positive and false negative results. Although not perfect and still under development, using image findings to target regions with the highest probability of advanced cancer has great potential. Even though no current imaging method can absolutely differentiate benign from malignant lesions, imaging could point to abnormalities that should be biopsied.
One of the simplest methods of biopsy targeting is MRI-TRUS image fusion. With this method, MRI is acquired ahead of time, the biopsy is guided as usual based on the TRUS, but the MRI is fused (registered) to the interventional ultrasound for CSR targeting. Associated biopsy technologies include probe tracking devices such as magnetic sensors (Logiq-E9 system, GE Healthcare, Waukesha, Wis.) and positioning arms (Artemis, Eigen, Grass Valley, Calif.). Several clinical studies reported increased detection rates of significant cancer by CSR targeting. Technically, the accuracy of these systems relies on challenging cross-modality image-to-image registration and deformable registration methods. Images had been previously acquired using MRI, a different imaging modality than TRUS, with the patient in a different position and endorectal MRI coil compressing the gland. At biopsy, the TRUS probe also deforms the gland but differently and dynamically. These differences contribute to targeting errors that are difficult to quantify. Also, the means of verifying the registration are very limited, especially after the initial alignment. MRI-TRUS fused biopsy methods offer logistic advantages, maintain the traditional use of TRUS for biopsy, and are likely superior to traditional systematic methods. Yet their navigation requires further validation and it remains to be tested if these are sufficiently accurate to make a clear clinical difference.
A more involved but promising method of CSR targeting is to directly use the MRI for guiding the intervention, interventional MRI-guided biopsy. The main claim of this approach is a potentially superior targeting accuracy, by eliminating several error components such as pre-acquired to interventional image differences, image differences between the imaging modalities, and image fusion errors.
A few groups investigated the use of manually operated needle-guide devices in the MRI scanner. Several high-dose brachytherapy cases using a needle-guide template registered to the MRI have been performed at the NIH clinical center (Bethesda, Md.). Transperineal biopsy and brachytherapy procedures were performed at the Brigham and Women's Hospital (Boston, Mass.) in a 0.5T open MRI scanner. They also reported a transperineal prostate biopsy in a patient with recurrent PC after brachytherapy and showed that MRI guidance was useful for targeting. In Germany, two studies reported MRI guided biopsies in patients with elevated PSA levels and without previous TRUS guided biopsies and for repeat biopsies. A plastic transrectal biopsy device that allows manual angulation of a needle guide was developed by Invivo (Schwerin, Germany). But, its operation is time consuming and it can't be used with an endorectal coil, which limits the quality of prostrate imaging. A more advanced biopsy device was used at the NIH in a closed-bore 1.5T scanner. This incorporated an imaging coil, special position tracking coils, and a needle guide. They showed improved cancer detection in MRI-guided biopsies when the MRI-guided biopsy was not immediately following the TRUS-guided biopsy. But commonly, the manual devices were difficult to operate due to the limited access within the scanner and numerous table moves were required to access the patient.
A noticeable solution to guide the needle remotely in the MRI scanner is to employ robotic assistance. However, making a robot that can operate safely and accurately in the MRI scanner without being influenced by and without interfering with the functionality of the imager has been a very challenging engineering task.
Why is it Challenging to Make MRI Robots?
MRI scanners use magnetic fields of very high density (3 Tesla becoming common), with pulsed magnetic and radio frequency fields. Within the imager, ferromagnetic materials are exposed to very high magnetic interaction forces and heating may occur in conductive materials by electromagnetic induction. The use of electricity may cause interference leading to signal to noise attenuation, signal distortions, and image artifacts. As such, most of the components commonly used in robotics may not be used in close proximity of the MRI. For example, the ubiquitous electromagnetic motor is clearly MRI unsafe because it functions based on magnetism.
MRI-Safe, MRI-Conditional, and MRI-Unsafe ASTM Classification:
The American Society for Testing and Materials (ASTM) has set a series of standards to test (ASTM F2213, F2182, F2119) and classify (ASTM F2503) devices for the MRI environment. In short, devices are:    MRI-Safe  Is an item that poses no known hazards in all MR environments.    MRI-Conditional  Is an item that has been demonstrated to pose no known hazards in a specified MR environment with specified conditions of use. Field conditions that define the specified MR environment include field strength, spatial gradient, dB/dt (time rate of change of the magnetic field), radio frequency (RF) fields, and specific absorption rate (SAR).    MRI-Unsafe  Is an item that is known to pose hazards in all MR environments.
What are Ideal “MRI Safe” Materials and Energy Types?
Several non-ferrous metals such as titanium and nitinol have been found to be MRI-Conditional for small size parts and are used in commercial MRI passive devices (Biopsy needles for example). However, for noninterference with electro-magnetism the ideal materials should be not only nonmagnetic but also dielectric, such as plastic, rubber, and glass. Interestingly, carbon fiber is not MRI-Safe because it is a good electrical conductor. From the energetic point of view, the use of electricity will likely exclude the MRI-Safe option, because currents generate electromagnetic waves and require wires that are not dielectric. Electric devices could be MRI-Conditional at best. Pneumatics and light on the other hand are ideal MRI-Safe energy choices, because they are completely decoupled from electromagnetism.
Most previous attempts to make MRI-guided robots used piezoelectric actuators (motors, also called ultrasonic). These are magnetism free but use metallic components and electricity which typically affect the quality of MR images. Even without power, it was shown that the wiring may debase the signal-to-noise-ratio by as much as 50%. Electric screening and filtering solutions have been employed to cope with these problems and incremental gain was progressively achieved. Two representative examples of piezo-actuated robots are the Brigham and Women's Hospital (Boston, Mass.) system for open-MRI which had to be located distal above the scanner, and the recent NeuroArm from the University of Calgary (Canada) which normally operates in the MRI room but not in the scanner. Moreover, piezoelectric robots may only be MRI-Conditional but not MRI-Safe. Scientifically, since PCa imaging is still under development, it is preferable that no image artifact compromise should be made to use the biopsy device in the scanner and that MRI sequences should not be limited to certain types that provide less problems with the device.
Hydraulic actuation may be MRI-Safe if properly constructed of nonmetallic materials. However, fluid leakage is difficult to control, especially when nonmetallic components are used. For medical applications this raises contamination and sterility concerns. As such, hydraulic MRI robot approaches maintained the use of metallic components.
Pneumatic actuation is a fundamentally flawless MRI-safe option. But, the major limitation of classic pneumatic actuators is their notoriously difficult motion control. Pneumatic servo control is a very delicate problem, because the compressibility of the air and the stiction of the piston make the system highly nonlinear and hardly manageable. Pneumatic servo control in the MRI is even more intricate because long hoses are needed to connect them to pneumatic valves, which are typically located distal from the scanner. Moreover, pneumatic cylinders have another major problem for medical applications: they are direct drive actuators. If they malfunction, direct drives may swiftly spring off, fully and quickly unwinding and potentially hurting the patient or personnel. Medical applications require small, slow, precise, and safe actuation. A direct-drive actuator that is also hardly controllable represents a safety concern. As such, researchers devised a good solution implementing breaks for safety. But unfortunately, due to all the additional complexity, the robots still included metallic components and were shown to debase the signal to noise ratio of the MRI. The former Innomotion company (Germany) devised a very ingenious purpose built pneumatic cylinder to help its control. This increased the sliding friction relative to the stiction in order to reduce the unfavorable influence of the later in servo-control. Unfortunately, this cylinder remained highly sensitive to disturbances such as small temperature changes.
A pneumatic turbine based motor was recently reported from the Nijmegen Medical Centre in the Netherlands and the device is entirely built of nonmetallic components. This represents a very promising MRI-safe engineering solution. The device applies to direct MRI-guided endorectal prostate biopsy and is the first actuated device for the application to be tested clinically. But apparently the actuators of device are not encoded yet, or the feedback is not being used for control so that the device is not a robot but remotely controlled by the physician observing the MRI. This is an especially difficult task because the MRI has relatively long acquisition times.
Hitherto, very few interventional MRI-guided prostate biopsy devices have been tested clinically in very few patients. Yet, these have shown the feasibility of interventional MRI and CRS biopsy targeting. The rational of biopsy targeting to improve selectively the detection of significant PCa appears to be sound, but further device refinements and clinical validations are needed to evaluate its clinical role. Accordingly, there is a need in the art for biopsy targeting to improve the detection of PCa.